Methods Of Treating Depression Using Orexin-2 Receptor Antagonists

ABSTRACT

The present disclosure is directed to, inter alia, methods of treating a subject suffering from or diagnosed with depression, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1  to R 4  are described herein and wherein the compound is administered prior to sleep.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/306,487, filed Mar. 10, 2016, which is incorporated by referenceherein.

TECHNICAL FIELD

The present disclosure is directed to, among other things, methods forthe treatment of depression.

BACKGROUND

Orexins (also known as hypocretins) are neuropeptides expressed byneurons in the perifornical area, the dorsomedial hypothalamus and thelateral hypothalamus (de Lecea et al., 1998; Proc. Natl. Acad. Sci.U.S.A. 95, 322-327; Sakaurai et al, 1998, Cell 92, 573-585). Orexinergicneurons project to many areas of the brain including other hypothalamicnuclei, the midline paraventricular thalamus, brain stem nuclei, theventral tegmental area and nucleus accumbens shell. (Peyron et al.,1998, J. Neurosci. 18, 9996-10016) Orexin neuropeptides, classified aseither orexin-A or orexin-B, bind to the seven transmembrane G-proteincoupled receptors orexin-1 (OX1R) and orexin-2 (OX2R) (de Lecea et al.,1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al, 1998,Cell 92, 573-585). While orexin-A is non-selective for OX1R and OX2R,orexin-B shows higher affinity for OX2R (Sakaurai et al, 1998, Cell 92,573-585). Orexin receptor antagonists are classified as single orexinreceptor (SORAs) or dual receptor antagonists (DORAs).

Hypothalamic orexinergic neurons expressing discharge during activewake, are virtually silent during non-rapid eye movement sleep and showtransient discharges during rapid eye movement sleep (Lee, 2005, J.Neuroscience 25(8): 6716-6720; Takahashi, 2008, Neuroscience, 153:860-870). This activity pattern supports the notion that the orexins areendogenous, potent, arousal (wakefulness)-promoting peptides. Studiesusing single unit recordings also show that OX-containing neurons arepreferentially activated during rewarding appetitive behaviors (Hassaniet al., 2016. J Neuroscience 36(5): 1747-1757). However, orexins arealso hypothesized to play a role in excessive arousal (e.g.hypervigilance, anxiety, somatic tension, agitation and/or excessiverumination) which occurs in subsets of patients with mood disorders. Todate, it is believed that intrinsic antidepressant activity of aselective OXR2 antagonist has not been explored clinically.

As is known in the art, clinically significant improvement in symptomsof depression in subjects diagnosed with Major Depressive Disorder (MDD)may take 4-6 weeks after the initiation of treatment with currentlyavailable antidepressants. Therefore, it is not expected that MDDsubjects would benefit from shorter periods of antidepressant therapy,especially 2 weeks or less. There remains a high, unmet medical need toprovide an effective treatment for depression.

SUMMARY

The general description and the following detailed description areexemplary and explanatory only and are not restrictive of thedisclosure, as defined in the appended claims. Other aspects of thepresent disclosure will be apparent to those skilled in the art in viewof the detailed description of the disclosure as provided herein.

In one aspect, methods of treating a subject suffering from or diagnosedwith depression are provided. These methods comprise administering to asubject in need of such treatment an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof, whereinR¹-R⁴ are defined herein, and wherein the compound of formula (I) isadministered prior to sleep.

In another aspect, the subject treated according to the methodsdescribed herein is not suffering from or diagnosed with an insomniadisorder.

In a further aspect, the compound of formula (I) is administered atnight according to the methods described herein.

BRIEF DESCRIPTION OF THE FIGURES

The present disclosure may be understood more readily by reference tothe following detailed description taken in connection with theaccompanying figures and examples, which form a part of this disclosure.It is to be understood that this disclosure is not limited to thespecific devices, methods, applications, conditions or parametersdescribed and/or shown herein, and that the terminology used herein isfor the purpose of describing particular embodiments by way of exampleonly and is not intended to be limiting of the claimed invention. Also,as used in the specification including the appended claims, the singularforms “a,” “an,” and “the” include the plural, and reference to aparticular numerical value includes at least that particular value,unless the context clearly dictates otherwise. When a range of values isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms another embodiment. Allranges are inclusive and combinable.

The summary, as well as the following detailed description, is furtherunderstood when read in conjunction with the appended figures:

FIGS. 1-2 are the mean plasma concentration-time profiles for[5(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanone(Compound A) formulations.

FIGS. 3-8 are the composite plasma concentration-time profiles forCompound A formulations.

FIGS. 9-11 are the individual and mean plasma pharmacokinetic parametersversus treatment plots for Compound A formulations.

FIG. 12 is a line graph of the time (min) from lights out to 10 minutesof sleep vs. the change from baseline at day 10/11.

FIG. 13 is a line graph of the time (min) of total sleep vs. the changefrom baseline at day 10/11.

FIG. 14 is a line graph of the latency to persistent sleep (LPS) changein Hamilton Depression Rating Scale (HAM-D₆) score from baseline at day10/11 vs. the HAM-D₆ change from baseline at day 11.

FIG. 15 is a line graph of the total sleep time (TST) change in HAM-D₆score from baseline at day 10/11 vs. the HAM-D₆ score change frombaseline at day 11.

FIG. 16 is the process flow chart regarding the preparation of thetablets used herein.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS I. Definitions

The term “depression” includes major depressive disorder, persistentdepressive disorder, depression associated with bipolar disorder (akabipolar depression), seasonal affective disorder, psychotic depression,postpartum depression, premenstrual dysphoric disorder, situationaldepression, anhedonia, melancholy, mid-life depression, late-lifedepression, depression due to identifiable stressors, treatmentresistant depression, or combinations thereof. In certain embodiments,the depression is major depressive disorder. In other embodiments, themajor depressive disorder is with melancholic features or anxiousdistress.

The methods described herein are useful in the treatment of the core (orpsychic) symptoms of depression. These symptoms include depressed moodand loss of interest or pleasure in nearly all activities.

The term “sleep onset” refers to the transition from wakefulness intonon-rapid eye movement (NREM) sleep; and “sleep” generally refers tonon-rapid eye movement (NREM) or rapid eye movement (REM) sleep.

The term “awake” describes a reasonably alert state of consciousnesscharacterized by alpha and beta waves as detected byelectroencephalogram, voluntary rapid eye movements and/or eye blinks.In other embodiments, an awake state may be characterized as the absenceof NREM or REM sleep.

The term “night” includes the period of time from sunset to sunrise,occurring once each twenty-four hours. In some embodiments, night refersto a timeframe in a twenty-four period in a day that precedes sleep by asubject.

An “insomnia disorder” refers to a diagnosis using criteria found in theAmerican Psychiatric Association's fifth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-V) and the Third Edition ofthe World Health Organization's International Classification of SleepDisorders (ICSD-3). In some embodiments, an “insomnia disorder” includesthe difficulty initiating or maintaining sleep and waking too earlyand/or obtaining non-restorative sleep, where the sleep difficultyresults in some form of daytime impairment.

Some of the quantitative expressions given herein are not qualified withthe term “about”. It is understood that whether the term “about” is usedexplicitly or not, every quantity given herein is meant to refer to theactual given value, and it is also meant to refer to the approximationto such given value that would reasonably be inferred based on theordinary skill in the art, including approximations due to theexperimental and/or measurement conditions for such given value.

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and include theadministration of a compound described herein to prevent the onset ofthe symptoms or complications, alleviate the symptoms or complications,or eliminate the disease, condition, or disorder. Similarly, “treatment”is used to encompass (a) reduction in the frequency of one or moresymptoms; (b) reduction in the severity of one or more symptoms; (c) thedelay or avoidance of the development of additional symptoms; and/or (d)delay or avoidance of the development of the disorder or condition, orany combination thereof.

As used herein, unless otherwise noted, the terms “subject” and“patient” may be used interchangeably and refer to an animal, preferablya mammal, most preferably a human, who has been the object of treatment,observation or experiment. In some embodiments, the subject or patienthas experienced and/or exhibited at least one symptom of the disease ordisorder to be treated and/or prevented. One skilled in the art willfurther recognize that the methods of treatment are directed to subjectsor patients in need of such treatment, prevention or dosing regimen,more particularly to subjects or patients diagnosed with or exhibitingat least one symptom of depression (preferably, meeting the criteria formajor depressive disorder or episode) regardless of type or underlyingcause. In further embodiments, the subject is not suffering from ordiagnosed with an insomnia disorder.

One skilled in the art will recognize that wherein methods of preventionare described, a subject in need thereof (i.e. a subject in need ofprevention) shall include any subject who has experienced or exhibitedat least one symptom of the disorder, disease or condition to beprevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical profession to be at risk of developing said disorder, disease orcondition. For example, the subject may be deemed at risk of having newepisodes of depression (and therefore in need of secondary prevention orpreventive treatment) as a consequence of the subject's medical history,including, but not limited to, family history, pre-disposition,co-existing (comorbid) disorders or conditions, genetic testing, and thelike.

Further, some of the quantitative expressions herein are recited as arange from about value X to about value Y. It is understood that whereina range is recited, the range is not limited to the recited upper andlower bounds, but rather includes the full range from about value Xthrough about value Y, or any value or range of values therein.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

II. The Compounds

As discussed above, the compounds described herein are orexin-2antagonists and may be used in the treatment of depression. In someembodiments, the compounds are administered such that they have a timeto maximal plasma concentration of less than about 3 hours, less thanabout 2 hours, and preferably less than about 1 hour, i.e., less thanabout 45 minutes, less than about 30 minutes, less than about 15minutes, among others. In other embodiments, the compound has anelimination half-life of about 4 hours and typically less than about 4hours. For example, certain compounds of the present disclosure have ahalf-life of about 2 to about 3 hours, e.g., about 2 hours, about 2.1hours, about 2.2 hours, about 2.3 hours, about 2.4 hours, about 2.5hours, about 2.6 hours, about 2.7 hours, about 2.8 hours, or about 2.9hours to about 3 hours. Given the short half-life, the amount of thecompound remaining in the subject upon waking is typically below thethreshold required for pharmacodynamic effect. For example, thecompounds of the present disclosure typically have a pharmacodynamiceffect from a dose level greater than about 5 mg.

In certain embodiments, the compound has the structure of formula (I):

R¹ is C₁₋₄ alkyl. In some embodiments, R¹ is CH₃.

R² is C₁₋₄ alkyl. In some embodiments, R² is CH₃.

R³ is H or halogen. In some embodiments, R³ is halogen. In otherembodiments, R³ is fluorine. In further embodiments, R³ is H.

R⁴ is H or C₁₋₄ alkoxy. In some embodiments, R⁴ is H. In furtherembodiments, R⁴ is C₁₋₄alkoxy. In other embodiments, R⁴ is methoxy.

“Alkyl” refers to a straight- or branched-chain alkyl group having from1 to 12 carbon atoms in the chain. Examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from5 to 7 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic ring structure that issaturated or partially saturated and has from 4 to 7 ring atoms per ringstructure selected from carbon atoms and up to two heteroatoms selectedfrom nitrogen, oxygen, and sulfur. The ring structure may optionallycontain up to two oxo groups on sulfur ring members. Illustrativeentities, in the form of properly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, and heterocycloalkyl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

“Alkoxy” includes a straight chain or branched alkyl group with aterminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,and so on.

“Halogen” represents chlorine, fluorine, bromine or iodine.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments for which each and everyone of the number of carbon members, from i to j including i and j, isindependently realized. By way of example, the term C₁₋₃ refersindependently to embodiments that have one carbon member (C₁),embodiments that have two carbon members (C₂), and embodiments that havethree carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any formula given herein is intended to represent a compound having astructure depicted by the structural formula as well as certainvariations or forms. In particular, a compound of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.

The compounds may include those described in U.S. Pat. No. 8,653,263 andUS Patent Publication No. 2014/0171430, both of which are incorporatedherein by reference. In some embodiments, the compound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanoneor a pharmaceutically acceptable salt thereof. In other embodiments, thecompound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone.In further embodiments, the compound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanonehydrochloride. In yet other embodiments, the compound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanoneor a pharmaceutically acceptable salt thereof. In still furtherembodiments, the compound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.In certain embodiments, the compound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanonehydrate. In other embodiments, the compound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanonehydrochloride hydrate. In further embodiments, the compound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanonehydrobromide hydrate.

Additionally, any formula given herein is intended to refer also tohydrates, solvates, and polymorphs of such compound, and mixturesthereof, even if such forms are not listed explicitly. A compound ofFormula (I) or pharmaceutically acceptable salts of a compound ofFormula (I) may be obtained as solvates. Solvates include those formedfrom the interaction or complexation of a compound with one or moresolvents, either in solution or as a solid or crystalline form. In someembodiments, the solvent is water and then the solvates are hydrates. Inaddition, crystalline forms of a compound of Formula (I) orpharmaceutically acceptable salts of a compound of Formula (I) may beobtained as co-crystals. In certain embodiments, a compound of Formula(I) is obtained in a crystalline form. In other embodiments, acrystalline form of a compound of Formula (I) is cubic in nature. Inother embodiments, pharmaceutically acceptable salts of compounds ofFormula (I) are obtained in a crystalline form. In still otherembodiments, compounds of Formula (I) are obtained in one of severalpolymorphic forms, as a mixture of crystalline forms, as a polymorphicform, or as an amorphous form. In other embodiments, a compound ofFormula (I) converts in solution between one or more crystalline formsand/or polymorphic forms.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds described herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²⁵I, respectively. Such isotopically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or an I¹²³ for SPECTstudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements. Isotopically labeled compounds describedherein and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

Also included are pharmaceutically acceptable salt of a compound ofFormula (I) and of the specific compounds exemplified herein, andmethods of treatment using such salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn,“Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72,S. M. Berge, “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, andHandbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahland Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples ofpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

The desired pharmaceutically acceptable salt may be prepared by anysuitable method available in the art, for example, treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoricacid, and the like, or with an organic acid, such as acetic acid,phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbicacid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid,valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as mandelic acid, citric acid, or tartaricacid, an amino acid, such as aspartic acid, glutaric acid, or glutamicacid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid,naphthoic acid, or cinnamic acid, a sulfonic acid, such aslaurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid,ethanesulfonic acid, any compatible mixture of acids such as those givenas examples herein, and any other acid and mixture thereof that areregarded as equivalents or acceptable substitutes in light of theordinary level of skill in this technology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondary,or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-D-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Pharmaceutically acceptable prodrugs of a compound of Formula (I) andtreatment methods employing such pharmaceutically acceptable prodrugsare also contemplated. The term “prodrug” means a precursor of adesignated compound that, following administration to a subject, yieldsthe compound in vivo via a chemical or physiological process such assolvolysis or enzymatic cleavage, or under physiological conditions(e.g., a prodrug on being brought to physiological pH is converted tothe compound of Formula (I). A “pharmaceutically acceptable prodrug” isa prodrug that is non-toxic, biologically tolerable, and otherwisebiologically suitable for administration to the subject. Illustrativeprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in “Design of Prodrugs”, ed. H.Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three, or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, omithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆alkyl)esters. Preferred esters include methyl esters. Prodrugs may also beprepared by derivatizing free hydroxy groups using groups includinghemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, following procedures such as thoseoutlined in Fleisher, Adv. Drug Delivery Rev. 1996, 19, 115-130.Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described inRobinson, J. Med. Chem. 1996, 39(I), 10-18. Free amines can also bederivatized as amides, sulfonamides, or phosphonamides. All of theseprodrug moieties may incorporate groups including ether (—O—), amine(—N—), and carboxylic acid (COO—) functionalities.

III. Compositions

The compounds described herein, including the compounds of formula (I),may be formulated as a pharmaceutical composition to administration to asubject. Accordingly, a pharmaceutical composition may comprise (a) aneffective amount of at least one compound described herein and (b) apharmaceutically acceptable excipient. A “pharmaceutically acceptableexcipient” refers to a substance that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to asubject, such as an inert substance, added to a pharmacologicalcomposition or otherwise used as a vehicle, carrier, or diluent tofacilitate administration of an agent and that is compatible therewith.Examples of excipients include calcium carbonate, calcium phosphate,various sugars and types of starch, cellulose derivatives, gelatin,vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the compounds described herein may be prepared usingsuitable pharmaceutical excipients and compounding techniques known orthat become available to those skilled in the art. The compositions maybe administered in the inventive methods by a suitable route ofdelivery, e.g., oral, parenteral, rectal, topical, ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, orliquid preparations. In some embodiments, the compositions areformulated for intravenous infusion, topical administration, or oraladministration. In certain embodiments, the compositions are formulatedfor immediate release.

For oral administration, the compounds can be provided in the form oftablets or capsules, or as a solution, emulsion, or suspension. Incertain embodiments, the compounds may be taken with food.

Oral tablets may include a compound mixed with pharmaceuticallyacceptable excipients such as inert fillers, diluents, disintegratingagents, binding agents, lubricating agents, sweetening agents, flavoringagents, coloring agents, glidants and preservative agents. Suitableinert fillers include sodium and calcium carbonate, sodium and calciumphosphate, lactose, lactose monohydrate, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, hypromellose, and thelike. Exemplary liquid oral excipients include ethanol, glycerol, water,and the like. Starch, polyvinyl-pyrrolidone, sodium starch glycolate,microcrystalline cellulose, crospovidone (cross-linked polyvinylN-pyrrolidone or PVP), and alginic acid are suitable disintegratingagents. Binding agents may include hypromellose (hydroxypropylmethylcellulose or HPMC), starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid, or talc. The glidant,if present, may be silica (SiO₂) such as colloidal silica. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, the compound may be mixed with asolid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the compound with water, an oil such as peanut oil orolive oil, liquid paraffin, a mixture of mono and di-glycerides of shortchain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions, or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally containpharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The compounds described herein may also be administered by non-oralroutes. For example, the compounds may be formulated for rectaladministration. For parenteral use, including intravenous,intramuscular, or intraperitoneal routes, the compound may be providedin sterile aqueous solutions or suspensions, buffered to an appropriatepH and isotonicity or in parenterally acceptable oil. Suitable aqueousvehicles include Ringer's solution and isotonic sodium chloride. Suchforms will be presented in unit-dose form such as ampules or disposableinjection devices, in multi-dose forms such as vials from which theappropriate dose may be withdrawn, or in a solid form or pre-concentratethat can be used to prepare an injectable formulation. Illustrativeinfusion doses may range from about 1 to 1000 μg/kg/minute of thecompound, admixed with a pharmaceutical carrier over a period rangingfrom several minutes to several days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compound may utilizea patch formulation to affect transdermal delivery.

Compounds may alternatively be administered by inhalation, via the nasalor oral routes, e.g., in a spray formulation also containing a suitablecarrier.

VI. Methods of Treating Depression

As described herein, the inventors found a surprising, robustantidepressant effect when using the compounds described on subjectsdiagnosed with depression. Although not intending to be limited bytheory, it is believed that because the activity of orexin containingneurons is negligible during sleep (typically at night), theantidepressant efficacy of the compounds discussed herein is surprising.As disclosed herein, administration prior to sleep (typically at night)of the compounds of the disclosure is associated with statisticallysignificant antidepressant efficacy, with the efficacy not related tothe effect on sleep items.

Accordingly, methods of treating a subject suffering from or diagnosedwith depression are provided. These methods comprise administering to asubject in need of such treatment an effective amount of a compounddescribed herein. In certain embodiments, the compound is of formula(I).

The compound is preferably administered once daily and is administeredto the subject prior to sleep. For example, the compound is administeredwithin about 2 hours of sleep, within about 1 hour, or within about 30minutes before sleep. In other embodiments, the compound is administeredat least about 4 hours before the subject wakes or intends to wake fromsleep, including about 5 hours, about 5.5 hours, about 6 hours, about6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours,about 11 hours, about 11.5 hours, or about 12 hours before the subjectwakes or intends to wake from sleep. In certain embodiments, thecompound is administered at least 6 hours to about 12 hours before thesubject wakes or intends to wake from sleep. In preferred embodiments,the compound is administered at night.

After administration of the compound, the compound undergoes at leastone half-life before the subject wakes from sleep. In other embodiments,the compound undergoes at least two half-lives, and preferably at leastthree half-lives before the subject wakes from sleep.

Desirably, the compound is below the threshold required forpharmacodynamic effect after about 6 to about 8 hours afteradministration of the compound. This differs from antidepressants in theart which are designed to achieve a steady state concentration of theantidepressant in the patient. The methods described herein differ inthat after one to eight hours of administration of the drug, theconcentration of the drug will fall below pharmacodynamic levels andremain at those levels for the remainder of the 24-hour treatment perioduntil the next dose of drug is administered.

Therapeutically effective amounts for the compounds described hereininclude amounts that elicit the biological or medicinal response in atissue system, animal or human that is being sought by a researcher,veterinarian, medical doctor, or other clinician, which includesalleviation of the symptoms of the disease or disorder being treated.Optimal dosages to be administered may be readily determined by thoseskilled in the art, and may vary with the mode of administration, thestrength of the preparation and the advancement of the diseasecondition. Such factors including the particular patient being treated,including patient's sex, age, weight, diet, time of administration andconcomitant diseases, among others. In certain embodiments, theeffective amount of each dose of the compounds described herein is about0.001 to about 200 mg of compound per kg of subject's body weight perday, about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in singleor divided dosage units (examples of such dosage units include 2.5 mg, 5mg, 10 mg, and 20 mg tablets). For a 70-kg human, an illustrative rangefor a suitable dosage amount is from about 0.05 to about 7 g/day, orabout 0.2 to about 2.5 g/day.

The effective amount of the compound described herein may also bedescribed without reference to the weight of the subject. Accordingly,the effective amount of the compound is about 10 to about 60 mg. In someembodiments, the effective amount of the compound is about 10 mg, about15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40mg, or within a range defined by any two of these values.

The effective amount of the compound may be administered in a singledaily dose. In further embodiments, the compound is administered dailyand one or more symptoms of the depression is reduced or amelioratedwithin about 11 days of a first administration, i.e., day 1.

Frequency adjustment can be accomplished by a one-time switch infrequency or may be determined over two or more administrations. Bydoing so, the attending physician or the like may determine an optimalfrequency for administration and thereby tailor the administration tothe patient.

Also contemplated by these methods is the administration of rescue dosesof the compounds described herein. The term “rescue dose” as used hereinrefers to one or more additional doses of a compound described herein inaddition to the regularly prescribed dose. The amount of a compounddescribed herein in the rescue dose may be determined by the prescribingphysician or clinician and will depend on any of the factors discussedherein. In certain embodiments, the rescue dose of a compounds describedherein is the same as the effective dose used during the normaladministration schedule. In other embodiments, the rescue dose differsfrom the effective dose used during the normal administration schedule.

One skilled in the art will recognize that in the methods describedherein, the maintenance of the response in a patient may be determinedby for example, a clinician, physician, psychiatrist, psychologist, orother suitable medical professional. Additionally, maintenance of theantidepressant response may be established by for example, an absence ofrelapse of the depression (or one or more symptoms of the depression),an absence of the need for additional or alternate treatment(s) for thedepression, or an absence of the worsening of the depression. Thephysician or attending clinician may utilize any technique known in theart including, without limitation, general patient evaluation,diagnostic questionnaires, and evaluations such as the Clinical GlobalImpression-Severity (CGI-S) scale, EuroQol; 5 dimension; 5 level(EQ-5D-5L), Patient Health Questionnaire-9 Item (PHQ-9), SheehanDisability Scale (SDS), Inventory of Depressive Symptomatology-Clinicianrated, 30-item scale (IDS-C₃₀), Montgomery-Asberg Depression RatingScale (MADRS) questionnaire, Hamilton rating scale for depression (HAM-Dor HDRS) Beck Scale for Depression, or Quick Inventory of DepressiveSymptomology (QIDS). The frequency may be evaluated and/or changed ifthe score from one or more of the above-noted scales or questionnairechanges.

In addition, the compounds may be used in combination with additionalactive ingredients in the treatment of the above conditions. Theadditional active ingredients may be administered simultaneously,separately or sequentially. In some embodiments, the additional activeingredients are effective in the treatment of conditions, disorders, ordiseases mediated by orexin activity, such as another orexin modulatoror a compound active against another target associated with theparticular condition, disorder, or disease. The combination may serve toincrease efficacy (e.g., by including in the combination a compoundpotentiating the potency or effectiveness of a compound herein),decrease one or more side effects, or decrease the required dose of thecompound described herein or additional active agent. In certainembodiments, the additional active ingredient is an antidepressant. Inother embodiments, the additional active ingredient is a monoaminergicantidepressant.

Accordingly, the compound of formula (I) may be used in combination witha second antidepressant. The second antidepressant may be a conventionaldrug used to combat depression such as N-methyl-D-aspartate receptorantagonists, norepinephrine reuptake inhibitors, selective serotoninreuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs),reversible inhibitors of monoamine oxidase (RIMAs), serotonin andnoradrenaline reuptake inhibitors (SNRIs), noradrenergic and specificserotonergic antidepressants (NaSSAs), corticotropin releasing factor(CRF) antagonists, alpha-adrenoreceptor antagonists and atypicalantidepressants. In some embodiments, the N-methyl-D-aspartate (NMDA)receptor antagonist is ketamine including its racemates esketamine,arketamine, or combinations thereof. In further embodiments, thenorepinephrine reuptake inhibitor includes amitriptyline, clomipramine,doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline,nortriptyline, protriptyline, reboxetine, or pharmaceutically acceptablesalts thereof. In other embodiments, the selective serotonin reuptakeinhibitor includes fluoxetine, fluvoxamine, paroxetine, sertraline, orpharmaceutically acceptable salts thereof. In further embodiments, themonoamine oxidase inhibitor includes isocarboxazid, phenelzine,tranylcypromine, selegiline and pharmaceutically acceptable saltsthereof. In yet other embodiments, the reversible inhibitor of monoamineoxidase includes moclobemide or pharmaceutically acceptable saltsthereof. In still further embodiments, the serotonin and noradrenalinereuptake inhibitor includes venlafaxine or pharmaceutically acceptablesalts thereof. In other embodiments, the atypical antidepressantincludes bupropion, lithium, nefazodone, trazodone, viloxazine,sibutramine, or pharmaceutically acceptable salts thereof. In yetfurther embodiments, the second antidepressant includes adinazolam,alaproclate, amineptine, amitriptyline/chlordiazepoxide combination,atipamezole, azamianserin, bazinaprine, befuraline, bifemelane,binodaline, bipenamol, brofaromine, bupropion, caroxazone, cericlamine,cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil,deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine,estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen,idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine,lofepramine, medifoxamine, metapramine, metralindole, mianserin,milnacipran, minaprine, mirtazapine, monirelin, nebracetam, nefopam,nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane,pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine,setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine,thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin,tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidinezometapine, or pharmaceutically acceptable salts thereof; or St. John'swort herb, Hypericum perforatum, or extracts thereof.

In some embodiments, the compound of formula (I) is co-administered withesketamine. In further embodiments, the compound of formula (I) isadministered separately from esketamine such as, e.g., sequentially. Thecompound of formula (I) may be administered prior or subsequent toesketamine.

V. Kits

Also described herein are kits for administering one or more compoundsdescribed herein to a patient for the treatment of depression. Therepresentative kits include one or more dosage units comprising aneffective amount of one or more compounds described herein foradministration to a patient and at a given frequency.

The dosage unit may be formulated for delivery by any means. In certainembodiments, the dosage unit is formulated for oral, intravenous,intranasal, intramuscular, sublingual, transdermal, otic, or rectaldelivery. In certain embodiments, the dosage unit is formulated for oraldelivery.

The dosage unit may be formulated to contain any amount of a compounddescribed herein, depending on the route of administration. Accordingly,each dosage unit may comprise the required dosage for the patient or maycomprise a portion of a compound described herein which is required fora single dosage.

Also optionally included in the kits is a depression symptom ratingscale questionnaire. The questionnaire may be for use by the patientalone or in combination with a physician. The questionnaire may beuseful for determining the level of depression of the patient at anystage of compound administration. In one embodiment, the questionnaireis one or more of the questionnaires noted herein.

Instructions for performing the claimed methods and administering thecompound may also be included in the kits described herein.

The kits may be organized to indicate a single formulation containing acompound described herein or combination of formulations, eachcontaining a compound described herein. The composition may besub-divided to contain appropriate quantities of a compound describedherein. The unit dosage can be packaged compositions such as packetedpowders, vials, ampoules, prefilled syringes, tablets, caplets,capsules, or sachets containing liquids.

The compound described herein may be a single dose or for continuous orperiodic discontinuous administration. For continuous administration, akit may include a compound described herein in each dosage unit. Whenvarying concentrations of a compound described herein, the components ofthe composition containing the compound described herein, or relativeratios of the compound described herein or other agents within acomposition over time is desired, a kit may contain a sequence of dosageunits.

The kit may contain packaging or a container with a compound describedherein formulated for the desired delivery route. The kit may alsocontain dosing instructions, an insert regarding the compound describedherein, instructions for monitoring circulating levels of the compound,or combinations thereof. Materials for using the compound may further beincluded and include, without limitation, reagents, well plates,containers, markers, or labels, and the like. Such kits may be packagedin a manner suitable for treatment of a desired indication

Other suitable components to include in such kits will be readilyapparent to one of skill in the art, taking into consideration thedesired indication and the delivery route. The kits also may include, orbe packaged with, instruments for assisting with theinjection/administration of the compound to the patient. Suchinstruments include, without limitation, an inhalant, syringe, pipette,forceps, measuring spoon, eye dropper, or any such medically approveddelivery means. Other instrumentation may include a device that permitsreading or monitoring reactions in vitro.

The compound may be provided in dried, lyophilized, or liquid forms.When reagents or components are provided as a dried form, reconstitutiongenerally is by the addition of a solvent. The solvent may be providedin another packaging means and may be selected by one skilled in theart.

A number of packages or kits are known to those skilled in the art fordispensing pharmaceutical agents. In certain embodiments, the package isa labeled blister package, dial dispenser package, or bottle.

Methods for optimizing a dosage of the compound for a patient having orbeing predisposed to depression also are provided. These methods caninclude (a) administering an effective amount of the compound to thepatient, (b) analyzing the effects of the compound, and (c)administering an effective amount of the compound to the patient lessfrequently of a defined duration.

VI. Aspects

The present disclosure comprises at least the following aspects.

Aspect 1. A method of treating a subject suffering from or diagnosedwith depression, comprising administering to a subject in need of suchtreatment an effective amount of a compound of formula (I):

wherein, R¹ is C₁₋₄ alkyl; R² is C₁₋₄ alkyl; R³ is H or halogen; and R⁴is H or C₁₋₄ alkoxy; or a pharmaceutically acceptable salt or hydratethereof, wherein the compound is administered prior to sleep.

Aspect 2. The method of aspect 1 wherein the subject is not sufferingfrom or diagnosed with an insomnia disorder.

Aspect 3. The method of any one of the preceding aspects, wherein R³ ishalogen.

Aspect 4. The method of any one of the preceding aspects, wherein R³ isfluorine.

Aspect 5. The method of any one of the preceding aspects, wherein R⁴ isH.

Aspect 6. The method of aspect 1 or 2, wherein R⁴ is C₁₋₄alkoxy.

Aspect 7. The method of any one of aspects 1, 2, or 6, wherein R⁴ ismethoxy.

Aspect 8. The method of any one of aspects 1, 2, 6, or 7, wherein R³ isH.

Aspect 9. The method of any one of the preceding aspects, wherein R¹ isCH₃.

Aspect 10. The method of any one of the preceding aspects, wherein R² isCH₃.

Aspect 11. The method of aspect 1 or 2, wherein the compound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanoneor a pharmaceutically acceptable salt thereof.

Aspect 12. The method of aspect 1, 2, or 11, wherein the compound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone.

Aspect 13. The method of aspect 1, 2, or 11, wherein the compound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanonehydrochloride.

Aspect 14. The method of aspect 1 or 2, wherein the compound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanoneor a pharmaceutically acceptable salt thereof.

Aspect 15. The method of any one of aspects 1, 2, or 12, wherein thecompound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Aspect 16. The method of any one of aspects 1 to 3, wherein the compoundis(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanonehydrate.

Aspect 17. The method of any one of aspects 1 to 3, wherein the compoundis(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanonehydrochloride hydrate.

Aspect 18. The method of any one of aspects 1 to 3, wherein the compoundis(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanonehydrobromide hydrate.

Aspect 19. The method of any one of the preceding aspects, wherein thecompound is administered at night.

Aspect 20. The method of any one of the preceding aspects, wherein thecompound is administered such that it has a time to maximal plasmaconcentration of less than about 1 hour.

Aspect 21. The method of any one of the preceding aspects, wherein thecompound has an elimination half-life of about 2 to about 3 hours.

Aspect 22. The method of any of the preceding aspects, wherein thecompound is administered to the subject about at least 4 hours beforethe subject intends to wake from sleep.

Aspect 23. The method of any one of the preceding aspects, wherein thecompound is below the threshold required for pharmacodynamic effectafter about 6 to about 8 hours after administration of the compound.

Aspect 24. The method of any one of the preceding aspects, wherein thecompound undergoes at least two half-lives before the subject wakes fromsleep.

Aspect 25. The method of any one of the preceding aspects, whereinsteady state of the compound is not achieved.

Aspect 26. The method of any one of the preceding aspects, wherein thecompound is administered daily.

Aspect 27. The method of any one of the preceding aspects, wherein thecompound is administered orally.

Aspect 28. The method of any one of the preceding aspects, wherein theeffective amount is about 0.05 to about 100 mg/kg/day.

Aspect 29. The method of any one of the preceding aspects, wherein theeffective amount is about 10 to about 40 mg.

Aspect 30. The method of any one of the preceding aspects, wherein thecompound is administered daily and one or more symptoms of thedepression is reduced or ameliorated within about 11 days of a firstadministration.

Aspect 31. The method of any one of the preceding aspects, wherein thedepression comprises major depressive disorder, persistent depressivedisorder, depression associated with bipolar disease, seasonal affectivedisorder, psychotic depression, postpartum depression, premenstrualdysphoric disorder, situational depression, anhedonia, melancholy,mid-life depression, late-life depression, depression due toidentifiable stressors, treatment resistant depression, or combinationsthereof.

Aspect 32. The method of aspect 31, wherein the depression is majordepressive disorder.

Aspect 33. The method of aspect 32, wherein the major depressivedisorder is with melancholic features or anxious distress.

Aspect 34. The method of any one of the preceding aspects, furthercomprising administering a second antidepressant.

Aspect 35. The method of aspect 34, wherein said second antidepressantis a norepinephrine reuptake inhibitor, selective serotonin reuptakeinhibitor, monoamine oxidase inhibitor, reversible inhibitor ofmonoamine oxidase, serotonin and noradrenaline reuptake inhibitor,noradrenergic and specific serotonergic antidepressant, corticotropinreleasing factor antagonist, alpha-adrenoreceptor antagonists, atypicalantidepressant, NMDA antagonist, or combinations thereof.

Aspect 36. The method of aspect 35, wherein said NMDA antagonist isesketamine.

The following Examples are set forth to aid in the understanding of thedisclosure, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLES Example 1

This example was performed to determine the plasma pharmacokinetic (PK)and bioavailability of a solid dose formulation of[5(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanone(Compound A) after single dose tablet administration relative to asuspension formulation. Also addressed are the effect of a semi-fastedcondition on the rate and extent of bioavailability of the solid doseformulation and tolerability of the solid and oral suspensionformulations.

(i) Reagents and Testing Parameters

[5(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanone(Compound A) was prepared as described in method B in Example 107 U.S.Pat. No. 8,653,263 with the exception that the recrystallization wasperformed using ethanol instead of an ethanol/2-propanol mixture.

The internal standard was isotope labeled[5(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanonewhich has the following structure.

The internal standard was prepared described in method B in Example 107U.S. Pat. No. 8,653,263 with the exception that step b was performedusing isotope labeled Intermediate 92, i.e.,2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole, bis-HClsalt, which was prepared using isotope labelled 2-chloro-4,6-dimethylpyrimidine of the following structure:

During each treatment period, blood samples were collected for PKmeasurements. Specifically, venous blood samples of 3 mL each werecollected for determination of Compound plasma concentrations. Thefollowing plasma Compound A PK parameters were estimated using theactual times of blood sampling:

-   -   C_(max) peak plasma concentration.    -   t_(max) time to reach the peak plasma concentration.    -   AUC_(last) area under the plasma concentration-time curve from 0        to t hours post study drug dosing, calculated by trapezoidal        summation (time t is the time of the last quantifiable        concentration C_(last)).    -   AUC_(∞) AUC_(last) extrapolated to infinity, calculated as        AUC_(last)+C_(last)/λ_(z).    -   λλ_(z) elimination rate constant, determined by linear        regression of the terminal points of the In-linear plasma        concentration-time curve.    -   t_(1/2) terminal half-life, defined as 0.693/λ_(z).    -   CL/F total clearance of drug after extravascular administration,        uncorrected for absolute bioavailability, calculated as        Dose/AUC_(∞).    -   Vd/F apparent volume of distribution after extravascular        administration, uncorrected for absolute bioavailability.

Compound A plasma levels were determined using LC-MS/MS using theequipment and parameters set forth in Tables 1-4.

TABLE 1 HPLC System Pump LC-10 Advp (Shimadzu) with SCL-10 Avp systemcontroller and DGI-14A on-line degasser Pressure limits (psi) 0-3500Pumping Mode Binary Total Flow (mL/min) 0.350 Initial pump B conc. (%)20.0 Column heater Shimadzu CTO10ACvp Oven temperature (° C.) 30.0Autosampler SIL HTc (Shimadzu) Injection Volume (μL) 2.00 CoolerTemperature (° C.) 4 Shimadzu SIL-HTc Properties Rinsing Volume (μL) 500Needle Stroke (mm) 47 Rinsing Speed (μL/s) 35 Sampling Speed (μL/s) 5.0Purge Time (min) 1.0 Rinse Dip Time (sec) 5 Rinse mode Before and afteraspiration Gradient Time (min) Module Events Parameter 1.50 Pumps Pump BConc. 50 1.51 Pumps Pump B Conc. 90 2.50 Pumps Pump B Conc. 90 2.51Pumps Pump B Conc. 20 3.00 Controller Stop

TABLE 2 Detector Detector Mass spectrometer API 4000 (AB Sciex) IonSource Turbo-ion spray Duration (min) 4.00 Polarity Positive MRMResolution Q1 unit Resolution Q3 unit Intensity threshold (cps) 0.00 CUR30.0 CAD 5.00 GAS 1 (psi) 40.0 GAS 2 (psi) 50.0 IS (V) 5000 Temperature(° C.) 600 Ihe On

TABLE 3 Mass Dependent Parameters Q1 Q3 DP CE CXP Time Compound MassMass (V) (V) (V) (ms) Compound A 408.2 190.0 80 39 13 300 InternalStandard 411.2 190.0 80 39 13 300 Compound B

TABLE 4 Blank Matrix Anti- Matrix Species coagulant Plasma Human EDTAAnalytical column XBridge BEH C18 column Dimensions (mm) 50 × 2.1Particle Size (μm)   3.5 Typical backpressure 1500 Pre-column/filterFrit filter HPLC Reagents Mobile phase A 0.1% formic acid in water Mixformic acid (2.00 mL) with water (2000 mL) Mobile phase B acetonitrileRinse Solvent 2-propanol:acetonitrile:water:formic acid (40:40:20:0.1vv/v/v/v) Mix propanol (400 mL) with acetonitrile (400 mL) with water(200 mL) and formic acid (1 mL) Dilution Solvent 0.1% formic acid inwater Mix formic acid (1.00 mL) with water (1000 mL) Stock Dilutiondimethylsulfoxide:acetonitrile (50:50, v/v) Solvent Mixdimethylsulfoxide (50.0 mL) with acetonitrile (50.0 mL) System Check0.1% formic acid in water:acetonitrile (80:20, v/v) Dilution Solvent Mix0.1% formic acid (80.0 mL) in water with acetonitrile (20.0 mL)

Two stock solutions were prepared for Compound A and one stock solutionfor internal standard Compound B according to the following.

-   -   Compound A Stock Solution: this solution was prepared by        dissolving Compound A (1.00 mg) in the Stock Dilution Solvent        (10.0 mL)    -   Compound A Overcurve Stock Solution: this solution was prepared        by dissolving Compound A (2.00 mg) in 2.00 mL of the Stock        Dilution Solvent (2.00 mL)    -   Compound B Stock Solution: this solution was prepared by        dissolving Compound B (1.00 mg) in 10.0 mL of the Stock Dilution        Solvent (2.00 mL).

Standard stock solutions were prepared for Compound A and the internalreference according to the following.

-   -   Compound A standard solution 1 (10.0 μg/mL): Compound A Stock        Solution (1000 μL) was combined with the Stock Dilution Solvent        (10.0 mL).    -   Compound A standard solution 2 (1.00 μg/mL): Compound A Stock        Solution (100 μL) was combined with the Stock Dilution Solvent        (10.0 mL).    -   Compound A Standard Solution 3 (0.100 μg/mL): Compound A Stock        Solution (10.0 μL) was combined with the Stock Dilution Solvent        (10.0 mL).    -   Compound B Working Solution (200 mg/mL): Compound B Stock        Solution (200 μL) was combined with the Stock Dilution Solvent        (100 mL).

Samples were prepared for testing using the following protocol:

-   -   (i) Plasma samples at room temperature were homogenized.    -   (ii) The samples were centrifuged for 5 minutes at about 2500×g        and 20° C.    -   (iii) The plasma sample (50.0 μL) was pipetted into a 1.2 mL        round well collection plate.    -   (iv) Stock Dilution Solvent (50.0 μL) was added to the blanks        and the internal standard working solution was added to all        other tube. Tubes were then vortexed for 10 seconds.    -   (v) Acetonitrile (100 μL) was added to each tube and the tubes        again vortex-mixed for 10 seconds.    -   (vi) Acetonitrile (250 μL) was further added to each tube and        the tubes again vortex-mixed for 60 seconds.    -   (vii) The samples were centrifuged for 5 minutes at about 2500×g        and 20° C.    -   (viii) The supernatant (50.0 μL) was transferred into a 1.2 mL        round well collection plate using the liquidator.    -   (ix) Formic acid (0.1%; 400 μL) in water was added to each tube        and the tubes vortex-mixed for 10 seconds.

Plots of the chromatograms and peak area integrations were carried outby Analyst (version 1.6.2, MDS Sciex, Concord, Canada). Calculationswere done using Watson 7.3 bioanalytical LIMS (Thermo FisherScientific).

(ii) Drug Compositions

The suspension containing Compound A was prepared by reconstituting apowder (100 mg Compound A) with hypromellose (5 mg/mL) solution toprovide an oral 5 mg/mL oral suspension of Compound A. The hypromelloseused for reconstitution is a 0.5% hypromellose solution in sterile waterfor injection.

The specific procedure for preparing the suspension follows:

-   -   (i) A powder containing Compound A is was added to a vial.    -   (ii) To achieve the desired concentration of the suspension, an        appropriate amount of 0.5% HPMC solution was added to the vial.    -   (iii) A clean stir bar was added to the vial.    -   (iv) Since it was necessary to suspend the drug substance, the        vial with spin bar was placed on a magnetic stir plate and the        speed was adjusted to gently create a vortex in the liquid. Once        a gentle vortex was achieved, the speed of the stir bar was        increased for a rapid vortex at 2500 RPM (about 2400 to about        2600).    -   (v) The composition was mixed for a minimum of about 24 to about        36 hours.    -   (vi) After mixing, the suspension was ready for use and the        required volume was withdrawn for dosing.

Tablets containing Compound A contained the components set forth inTable 5.

TABLE 5 Quantity/Unit Dose Component (in mg/tablet) (in % w/w) CompoundA 20 13.3 Lactose monohydrate 80 53.3 Microcrystalline cellulose 40.5 27Crospovidone 7.5 5 Silica colloidal 1 0.7 Magnesium stearate 1 0.7 Total150 100

The tablets were prepared as described in FIG. 16 and according to thefollowing direct compression process:

A. Screening & Blending

-   -   1. All materials were passed through a Quadro Comil using        07L039R03125 screen at 1000 rpm, with the exception of magnesium        stearate. The following sequence of adding materials to the        screen was followed:        -   (i) About ½ of the lactose monohydrate        -   (ii) Compound A        -   (iii) Colloidal Silicon dioxide        -   (iv) Crospovidone        -   (v) Microcrystalline Cellulose        -   (vi) About half of the lactose monohydrate    -   2. The mixture was blended for 20 minutes at 20 rpm.    -   3. Magnesium stearate was sifted through a #40 sieve.    -   4. The mixture of step 3 was blended for 5 minutes at 20 rpm.

B. Compression

The tablets were compressed using a rotary press fitted with a “D” type7.0 mm round shallow concave punches and appropriate dies. Thein-process parameters are set forth in Table 6.

TABLE 6 Tablet Parameters Limits Description White to off white circularbiconvex tablets, plain on both sides Friability not more than (NMT)1.0% Hardness 5.0-13.0 kp (target 8.0 kp) Disintegration Time NMT 15minutes Individual tablet weight variation 150 mg ± 7.5% (139.0-161.0mg) Group Weight of 10 tablets 1.5 g ± 5% (1.425 g-1.575 g) Thickness3.35 mm-3.75 mm (target 3.50 mm)

(iii) Measurement of PK Parameters

Eighteen male subjects between 18 and 55 years of age, inclusive, weretested. The subjects had not received a potent cytochrome P450(CYP)3Aand CYP2C19 inhibitor within 14 days or a period less than 5 times thedrug's half-life (whichever was longer) or a potent CYP3A or CYP2C19inducer within 30 days before study drug administration on Day 1 ofPeriod 1 were excluded.

Subjects received a single oral dose of 20 mg Compound A (suspension oras a solid dose formulation) on Day 1 of each of the 3 treatmentperiods. The total study duration for each subject (including screeningand follow-up visit) was to be about 7 to 8 weeks.

This study consisted of 3 phases: an eligibility screening examination(between 21 days and 2 days prior to first dose administration), a 3-waycrossover single dose open-label treatment phase which consisted of 3treatment periods separated by a washout period of at least 6 daysbetween dosing, and a follow-up visit (within 7 to 14 days after lastdose administration).

All subjects enrolled were randomly assigned to one of three Treatments:

-   -   Treatment A: 20 mg oral suspension formulation of Compound A        (fasted state)    -   Treatment B: 20 mg solid formulation of Compound A (fasted        state)    -   Treatment C: 20 mg solid formulation of Compound A (semi-fasted        state)

(iii) Results

A mixed-effect model was applied to the natural log transformed C_(max)and AUC. The model included sequence, period, treatment as fixedeffects, and subject as a random effect. For each of the parameters, thecomparisons included:

-   -   The solid dosage formulation (fasted) vs. the oral suspension        formulation (fasted)    -   The solid dosage formulation (fasted) vs. the solid dosage        formulation (semi-fasted)

Following oral administration, Compound A was rapidly absorbed andreached C_(max) with median t_(max) values ranging from 0.5 to 1.0 hour.Following C_(max), Compound A concentrations declined rapidly in amono-exponential manner (up to 12 hour postdose). Mean t_(1/2) valuesfor the suspension (fasted) and tablet (semi-fasted) were similar (˜2hours). However, mean t_(1/2) value for the tablet under fastingcondition was longer than expected (˜5 hours). Extended low levels ofplasma concentrations during the terminal phase were found in somesubjects resulting in t_(1/2) values ranging from 1.9 to 17.3 hours.See, FIGS. 1-11.

Example 2

This example was performed as a multi-center, double-blind,diphenhydramine and placebo-controlled study. Men and women with adiagnosis of MDD between the ages of 18 and 64, inclusive, wereenrolled. At screening, the subjects had a total score of ≧30 on theIDS-C₃₀, corresponding to moderate to severe depression.

Blood and saliva were collected for the assessment of biomarkers, amongothers. Venous blood samples (3 mL each) were collected in fastingcondition between 8:00 and 10:00 am for the determination of[5(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanoneplasma concentrations and biomarkers related to immune system activity,Hypothalamus pituitary adrenal (HPA) axis activation, neurotropicfactors and metabolic factors were measured. Pharmacokinetic (PK) bloodsamples also were collected. Plasma samples were analyzed to determineconcentrations of Compound A using LC-MS/MS. Saliva was collected forthe measurement of concentrations of cortisol. Saliva concentrations ofcortisol were added as a biomarker.

Forty-eight subjects were randomly assigned (in a 2:1:1 ratio) to 20 mgof Compound A, 25 mg diphenhydramine or placebo q.d. (once daily) in theevening over 10 days for women of child bearing potential (WOCBP) or 4weeks for males and women of non-child bearing potential (WONCBP). Thesubjects received the medication as capsules containing 1 tablet of 20mg Compound A, 1 tablet of 25 mg diphenhydramine or placebo. Males andWONCBP took 1 capsule every evening just before bedtime from Day 1 toDay 28. WOCBP took 1 capsule every evening just before bedtime from Day1 to Day 10. There were 2 follow up visits occurring at 3 and 14 days.

For the evaluation of symptoms of depression, assessments were done atscreening and during the study. Specifically, symptoms of depressionwere performed using the Mini International Neuropsychiatric Interview(MINI) 6.0 interview, or Hamilton rating scale for Depression-17(HDRS17). Also, polysomnography (PSG) was performed to quantify sleepstages including latency to persistent sleep (LSP) and total sleep time(TST). Thereafter, symptoms of depression were taking on days 11 and 29during treatment and days 3 and 14 following treatment. PSG was recordedovernight after the first and tenth dose administration of studymedication.

(i) Posology

Compound A was found to be an orally active, selective antagonist of theorexin-2 receptor. After oral administration of 20 mg, Compound A had ashort time to maximal plasma concentrations (T_(max)<1 hour) and wascharacterized by a short half-life (2-3 hours). Daytime administrationof Compound A induced somnolence in healthy subjects while nighttimeadministration reduced the latency to persistent sleep (LPS) andprolongs the total sleep time (TST) in subjects with insomnia disorder(ID). The magnitude of the effect of Compound A on LPS and TST isdirectly related to level of insomnia at baseline. See, FIGS. 12-15.

Nighttime administration (within 30 minutes before bedtime) resulted inintermittent exposure of Compound A to plasma. Thus, it was demonstratedthat repeated (10 days) daily dose administration did not result inaccumulation.

(ii) HDRS₁₇/HAM-D₆

A HDRS₁₇ total score was calculated by summing the 17 item scores takenduring the study. A HDRS₁₇ total score ranges from 0 to 52, with higherscores indicating greater severity of depression. In order to correctfor a possible effect of study medication on sleep, sleep-related itemswere removed from the HDRS₁₇ to calculate a (sleep item)-adjusted HDRS.Accordingly, an adjusted HDRS₁₇ total score was calculated by summingthe item scores excluding the 3 insomnia questions (4-Insomnia Early,5-Insomnia Middle and 6-Insomnia Late). A HDRS₁₇ adjusted total scoreranges from 0 to 46. A 6-item subscale from the HDRS₁₇ (HAM-D₆) wasanalyzed and provided information to core depressive symptoms and issensitive to treatment response. The six items included depressed mood,guilt feelings, work and interests, psychomotor retardation, psychicanxiety, and general somatics (tiredness and pains).

TABLE 7 Mean score ± standard deviation Compound Compound Diphen- Ahydramine Placebo 20 mg 25 mg Study Time (N = 12) (N = 22) (N = 13)Total Baseline 18.7 (5.71) 18.7 (4.65) 20.0 (5.12) HDRS₁₇ Day 11 Change−3.6 (4.03) −5.5 (3.86) −4.1 (3.66) from baseline Mean Baseline 13.7(4.98) 14.4 (3.36) 15.1 (4.41) Adjusted Day 11 Change −2.3 (3.03)  −4.5(2.76)* −2.3 (2.81) HDRS17 from baseline

The results in Table 7 illustrate that the improvement in the totalHDRS₁₇ observed after administration of 20 mg of Compound A is mostlyunrelated to changes in sleep (−5.5 versus −4.5 points) whereassleep-related changes appear to more important for diphenhydramine (−4.1versus −2.3).

The HAM-D₆ score was calculated by summing the 6 items scores, andranges from 0 to 22. Higher scores indicate greater severity of coresymptoms.

TABLE 8 Mean scores ± standard deviation Compound Compound Diphen- Ahydramine Placebo 20 mg 25 mg Score Time (N = 12) (N = 22) (N = 13) meanBaseline  4.3 (1.56) 4.8 (1.56)  5.1 (1.80) HDRS₁₇ Day 11 Change −0.8(1.40) −1.6 (1.50)  −0.9 (1.12) anxiety/ from baseline somati- zationfactor score Mean Baseline  9.0 (3.57) 10.4 (2.09)  10.6 (3.31) HAM-D₆Day 11 Change −1.5 (2.15)  −3.8 (2.22)** −1.8 (2.01) from baseline

The results in Table 8 illustrate that the change from baseline in theHDRS anxiety/somatization factor did not account for the observedimprovement in depression ratings in the Compound A group. However, thecore symptoms of depression (per HAM-D₆) did account for the observedimprovement in depression ratings in the Compound A group.

(iii) Polysomnography

The effects of study medication on polysomnography (PSG)-derivedparameters was evaluated overnight on Days 1/2 and 10/11. In addition,PSG was recorded up to and following a forced wake overnight on Day 5/6.Two screening PSG recordings were made and baseline values werecalculated as the average values recorded at Screening 1 and 2.

(a) Total Sleep Time (TST)

TST is defined as total minutes spent in rapid eye movement (REM) andnon-REM sleep. Compared to placebo, both Compound A and diphenhydramineincreased TST overnight on Day 1/2. Because of an increase in TST inplacebo-treated subjects on Day 10/11, the relative effect of Compound Aand diphenhydramine were less pronounced. See, Table 9. Although theoverall study population did not meet criteria for insomnia disorder(TST<360 minutes), individual subjects had baseline TST values as low as263 minutes. Thus, the population was mixed with respect to the presenceof insomnia disorder.

TABLE 9 Compound Compound A Diphenhydramine Placebo 20 mg 25 mg Time(min) (N = 12) (N = 22) (N = 13) Baseline 376 (56.2)  380 (50.1) 382(47.2) Day 1/2 Change  7.4 (52.07)  30.9 (54.06)  28.3 (33.92) frombaseline Day 10/11 Change 20.7 (64.44) 26.56 (56.11)  33.92 (46.01) from baseline

The effect of Compound A on TST is proportional to the TST duration atbaseline (FIG. 13). However, no relationship between the magnitude ofthe LPS change and the improvement in core depressive symptoms wasobserved (FIG. 15) supporting an antidepressant effect independent froman effect on insomnia.

(b) Latency to Persistent Sleep

LPS is defined as the elapsed time (in minutes) from lights out to 10minutes of continuous sleep. Compared to placebo, both Compound A anddiphenhydramine modestly reduced LPS overnight on Day 1/2. Because of adecrease in LPS in placebo-treated subjects overnight on Day 10/11, therelative effect of Compound A and diphenhydramine were less pronounced.See, Table 10. Overall, the study population was characterized by aprolonged (>20 minutes) LPS. Similar as for TST, the population wasmixed with respect to the presence of insomnia disorders at baselinewith LPS values as low as 4.5 minutes.

TABLE 10 Compound Compound A Diphenhydramine Placebo 20 mg 25 mg Time(min) (N = 12) (N = 22) (N = 13) Baseline 53.8 (40.12) 40.9 (22.62) 36.0 (19.20)  Day 1/2 Change  3.4 (46.39) 8.7 (36.04) 6.7 (26.40) frombaseline Day 10/11 Change 17.5 (51.40) 9.2 (30.41) 0.3 (30.57) frombaseline

The effect of Compound A on LPS is proportional to the LPS duration atbaseline (FIG. 12). However, no relationship between the magnitude ofthe LPS change and the improvement in core depressive symptoms wasobserved (FIG. 14) supporting an antidepressant effect independent froman effect on insomnia.

(iv) Summary

These results show that, compared to placebo and diphenhydramine, theantidepressant effect of Compound A was larger and clinically relevant.Surprisingly, the effect of Compound A was largely related to an effecton the core symptoms of depression and overall unrelated to its effecton sleep related items. The antidepressant effect was sustained at least14 days after treatment discontinuation. Of importance, improvementswere already observed on Day 11 (first assessment) and were sustainedupon treatment discontinuation.

Example 3

This example was performed to illustrate that Compound A may be used inan adjunctive therapy. Specifically, Compound A was administered tosubjects diagnosed with MDD (i) as a monotherapy and (ii) in combinationwith a known anti-depressant and the symptoms of depression of thesubjects evaluated using the HDRS17 and HAM-D6 scale

In Group 1, thirty seven subjects were randomly assigned (in a 2:1:1ratio) to 20 mg of Compound A, 25 mg diphenhydramine or placebo q.d. inthe evening over 10 days. In Group 2, ten subjects were randomlyassigned (in a 2:1:1 ratio) to 20 mg of Compound A, 25 mgdiphenhydramine or placebo q.d. in the evening over 10 days. Eachsubject in Group 2 also took an amount of antidepressant selected fromduloxetine, citalopram, paroxetine, or sertraline and as prescribed bytheir attending physician. For the evaluation of symptoms of depressionfor both groups, assessments were independently performed at screeningand on Day 11, i.e., one day after the study, using HDRS₁₇ and HAM-D₆ asdescribed in Example 2. The results of the evaluations are summarized inTables 11 and 12. In Tables 11-12, # denotes the Cohen effect size, *denotes P<0.05 (statistically significant), and ** denotes P<0.01.

TABLE 11 Mean scores ± SD Group I Compound Diphen- A hydramine Placebo20 mg 25 mg Scale Time (N = 8) (N = 18) (N = 11) HDRS17 Baseline 19.5(5.40) 19.4 (4.80) 21.5 (3.78) Day 11 Change −2.5 (4.14) −5.1 (3.97)−4.2 (4.00) from baseline Effect Size −0.64 Compound A vs Placebo^(#)Adjusted Baseline 14.4 (4.50) 14.9 (3.37) 16.4 (3.35) HDRS Day 11 Change−1.4 (3.29)  −4.3 (2.97)* −2.1 (3.02) from baseline Effect Size −0.93Compound A vs Placebo^(#) Anxiety- Baseline  4.4 (1.41)  5.1 (1.53)  5.5(1.51) Somati- Day 11 Change −0.8 (1.49) −1.6 (1.65) −0.8 (1.17) zationfrom baseline Factor Effect Size −0.51 Compound A vs Placebo^(#) HAM-D₆Baseline  9.6 (3.70) 10.8 (2.07) 11.7 (2.05) Day 11 Change −0.8 (2.25) −3.6 (2.33)** −1.7 (2.15) from baseline Effect Size −1.22 Compound A vsPlacebo^(#)

TABLE 12 Group 2 Compound Diphen- A hydramine Placebo 20 mg 25 mg (N =4) (N = 4) (N = 2) HDRS17 Baseline 17.0 (6.78) 15.5 (2.08) 11.5 (0.71)Day 11 Change −5.8 (3.20) −7.0 (3.37) −3.5 (0.71) from baseline EffectSize −0.37 Compound A vs Placebo^(#) Adjusted Baseline 12.3 (6.29) 11.8(1.89)  8.0 (1.41) HDRS Day 11 Change −4.3 (0.96) −5.5 (1.29) −3.5(0.71) from baseline Effect Size −1.06 Compound A vs Placebo^(#)Anxiety- Baseline  4.3 (2.06)  3.5 (1.00)  2.5 (0.71) Somati- Day 11Change −1.0 (1.41) −1.8 (0.50) −1.5 (0.71) zation from baseline FactorEffect Size −0.76 Compound A vs Placebo^(#) HAM-D₆ Baseline  7.8 (3.40) 8.8 (1.26)  4.5 (0.71) Day 11 Change −3.0 (0.82) −4.8 (1.50) −2.0(1.41) from baseline Effect Size −1.49 Compound A vs Placebo^(#)

These results illustrate that Compound A has antidepressant efficacy inuntreated and antidepressant drug-treated subjects with MDD supportingits efficacy as monotherapy and adjunctive therapy.

The disclosures of each patent, patent application, and publicationcited or described in this document are hereby incorporated herein byreference, in its entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the disclosureand that such changes and modifications can be made without departingfrom the spirit of the disclosure. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the disclosure.

What is claimed is:
 1. A method of treating a subject suffering from ordiagnosed with depression, comprising administering to a subject in needof such treatment an effective amount of a compound of formula (I):

wherein: R¹ is C₁₋₄ alkyl; R² is C₁₋₄ alkyl; R³ is H or halogen; and R⁴is H or C₁₋₄ alkoxy; or a pharmaceutically acceptable salt or hydratethereof, wherein the compound is administered prior to sleep.
 2. Themethod of claim 1 wherein the subject is not suffering from or diagnosedwith an insomnia disorder.
 3. The method of claim 1, wherein R³ ishalogen.
 4. The method of claim 3, wherein R³ is fluorine.
 5. The methodof claim 1, wherein R⁴ is H.
 6. The method of claim 1, wherein R⁴ isC₁₋₄alkoxy.
 7. The method of claim 6, wherein R⁴ is methoxy.
 8. Themethod of claim 1, wherein R³ is H.
 9. The method of claim 1, wherein R¹is CH₃.
 10. The method of claim 1, wherein R² is CH₃.
 11. The method ofclaim 1, wherein the compound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanoneor a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the compound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone.13. The method of claim 1, wherein the compound is5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanonehydrochloride.
 14. The method of claim 1 wherein the compound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanoneor a pharmaceutically acceptable salt thereof.
 15. The method of claim1, wherein the compound is(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone16. The method of claim 1, wherein the compound is administered atnight.
 17. The method of claim 1, wherein the compound is administereddaily.
 18. The method of claim 1, wherein the compound is administeredorally.
 19. The method of claim 1, wherein the effective amount is about10 to about 40 mg.
 20. The method of claim 1, wherein the depressioncomprises major depressive disorder, depression associated with bipolardisease, or treatment resistant depression.
 21. The method of claim 20,wherein the depression is major depressive disorder.
 22. The method ofclaim 20, wherein the depression is treatment resistant depression. 23.The method of claim 1, further comprising administering a secondantidepressant.
 24. The method of claim 23, wherein said secondantidepressant is a selective serotonin reuptake inhibitor, serotoninand noradrenaline reuptake inhibitor, or combinations thereof.